The proposed K22 award will support the transition of Li Li, M.D., Ph.D. from a mentored to an independent cancer genetic epidemiology investigator. During his mentored research supported by Damon Runyon Cancer Research Foundation, he has developed his expertise in cancer genetic/molecular epidemiology focusing on gene-environment interaction, and established a Kentucky SEER Registry-based incident case-control study of colon cancer. This study has already collected blood samples and data from over 580 cases and population controls, and it is anticipated that a total of 1,100 cases and controls will be accrued and available for this application by the end of his mentored Clinical Investigator Award. [unreadable] [unreadable] The K22 proposal will address the insulin resistance-colon cancer hypothesis by looking at the relation of insulin resistance syndrome as an integral entity with colon cancer using a novel structure equation model approach. This study holds promise of gaining novel and critical insight into the insulin resistance-colon link that might have been missed or distorted in studies using the conventional 'independent risk factor finding' regression analysis by treating each of the metabolic components of the syndrome as independent covariates. In addition, this K22 proposal will comprehensively evaluate SNPs and haplotypes of 9 candidate genes in three molecular pathways and two environmental factors, i.e., physical activity and non-steroidal anti-inflammatory drugs (NSAIDS), implicated in the development of insulin resistance and colon carcinogenesis. Specifically, this proposal has the following aims: 1) To assess the relation of insulin resistance syndrome as an integral entity with colon cancer; 2) To examine the relations of colon cancer with SNPs and haplotypes of 9 candidate genes in three molecular pathways: (i) insulin-growth hormone-IGF-insulin receptor substrate axis, (ii) inflammation, and (iii) adipogenesis; 3) To investigate the direct and indirect (i.e., mediated by insulin resistance) effects of these genetic and environmental factors on colon cancer. [unreadable] [unreadable] This research will fill current knowledge gaps in understanding the underlying link between insulin resistance resulting from long-term energy imbalance and colon cancer. It will set the stage for a planned full R01 application to seek national funding to expand the current effort to a fully powered study to tackle gene-environment joint action under the unifying theme of insulin resistance-colon cancer hypothesis. [unreadable] [unreadable] [unreadable]